R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine

Introduction: The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is one of the most attractive antidepressants for treatment-resistant major depressive disorder (MDD). Ketamine (or RS (±)-ketamine) is a racemic mixture containing equal parts of R (−)-ketamine and S (+)-ketamine.Methods: In this study, we examined the effects of R- and S-ketamine on depression-like behavior in juvenile mice after neonatal dexamethasone (DEX) exposure.Results: In the tail suspension test (TST) and forced swimming test (FST), both isomers of ketamine significantly attenuated the increase in immobility time, seen in DEX-treated juvenile mice at 27 and 29 h respectively, after ketamine injections. In the 1% sucrose preference test (SPT), both isomers significantly attenuated the reduced preference for 1% sucrose consumption in DEX-treated juvenile mice, 48 h after a ketamine injection. Interestingly, when immobility times were tested by the TST and FST at day 7, R-ketamine, but not S-ketamine, significantly lowered the increases in immobility seen in DEX-treated juvenile mice.Discussion: This study shows that a single dose of R-ketamine produced rapid and long-lasting antidepressant effects in juvenile mice exposed neonatally to DEX. Therefore, R-ketamine appears to be a potent and safe antidepressant relative to S-ketamine, since R-ketamine may be free of psychotomimetic side effects.